Bottom Line:
Mechanical ventilation and endotoxemia increased expression of inducible nitric oxide synthase (iNOS) mRNA and cytokine levels of interleukin (IL)-1β, IL-6 and keratinocyte-derived chemokine, and decreased IL-10, in the diaphragm; however, they had no effect on protein nitrosylation and 4-hydroxy-2-nonenal protein concentrations.Mechanical ventilation in combination with endotoxemia results in systemic and diaphragmatic inflammation.Levosimendan partly decreased markers of nitrosative and oxidative stress, but did not affect the inflammatory response.

Introduction: Controlled mechanical ventilation and endotoxemia are associated with diaphragm muscle atrophy and dysfunction. Oxidative stress and activation of inflammatory pathways are involved in the pathogenesis of diaphragmatic dysfunction. Levosimendan, a cardiac inotrope, has been reported to possess anti-oxidative and anti-inflammatory properties. The aim of the present study was to investigate the effects of levosimendan on markers for diaphragm nitrosative and oxidative stress, inflammation and proteolysis in a mouse model of endotoxemia and mechanical ventilation.

Results: Mechanical ventilation and endotoxemia increased expression of inducible nitric oxide synthase (iNOS) mRNA and cytokine levels of interleukin (IL)-1β, IL-6 and keratinocyte-derived chemokine, and decreased IL-10, in the diaphragm; however, they had no effect on protein nitrosylation and 4-hydroxy-2-nonenal protein concentrations. Levosimendan decreased nitrosylated proteins by 10% (P <0.05) and 4-hydroxy-2-nonenal protein concentrations by 13% (P <0.05), but it augmented the rise of iNOS mRNA by 47% (P <0.05). Levosimendan did not affect the inflammatory response in the diaphragm induced by mechanical ventilation and endotoxemia.

Conclusions: Mechanical ventilation in combination with endotoxemia results in systemic and diaphragmatic inflammation. Levosimendan partly decreased markers of nitrosative and oxidative stress, but did not affect the inflammatory response.

Mentions:
Blood pressure decreased progressively in both groups during 8 hours of MV (Figure 1) (P =0.09), despite volume therapy (0.3 ml/hr). Blood gas analysis results at the end of the experiments are shown in Table 1. The alveolar-arterial (A-a) oxygen gradient was high after 8 hours of MV in both groups (Table 1). During 8 hours of MV, 30% of the animals in the MV LPS group died (n =5: respectively, 4 hours, 5 hours and 5½ hours, and two mice died after 6 hours of MV). In the levosimendan-treated group, 12% (n =2) died before the end of the planned duration of MV (after 5 and 7½ hours of ventilation, respectively; P =0.2 between groups). Animals that did not survive until the end of the study were excluded from further biochemical analysis. Accordingly, 8 CON mice, 12 MV LPS mice and 14 MV LPS + L mice were included for biochemical analysis.Figure 1

Mentions:
Blood pressure decreased progressively in both groups during 8 hours of MV (Figure 1) (P =0.09), despite volume therapy (0.3 ml/hr). Blood gas analysis results at the end of the experiments are shown in Table 1. The alveolar-arterial (A-a) oxygen gradient was high after 8 hours of MV in both groups (Table 1). During 8 hours of MV, 30% of the animals in the MV LPS group died (n =5: respectively, 4 hours, 5 hours and 5½ hours, and two mice died after 6 hours of MV). In the levosimendan-treated group, 12% (n =2) died before the end of the planned duration of MV (after 5 and 7½ hours of ventilation, respectively; P =0.2 between groups). Animals that did not survive until the end of the study were excluded from further biochemical analysis. Accordingly, 8 CON mice, 12 MV LPS mice and 14 MV LPS + L mice were included for biochemical analysis.Figure 1

Bottom Line:
Mechanical ventilation and endotoxemia increased expression of inducible nitric oxide synthase (iNOS) mRNA and cytokine levels of interleukin (IL)-1β, IL-6 and keratinocyte-derived chemokine, and decreased IL-10, in the diaphragm; however, they had no effect on protein nitrosylation and 4-hydroxy-2-nonenal protein concentrations.Mechanical ventilation in combination with endotoxemia results in systemic and diaphragmatic inflammation.Levosimendan partly decreased markers of nitrosative and oxidative stress, but did not affect the inflammatory response.

Introduction: Controlled mechanical ventilation and endotoxemia are associated with diaphragm muscle atrophy and dysfunction. Oxidative stress and activation of inflammatory pathways are involved in the pathogenesis of diaphragmatic dysfunction. Levosimendan, a cardiac inotrope, has been reported to possess anti-oxidative and anti-inflammatory properties. The aim of the present study was to investigate the effects of levosimendan on markers for diaphragm nitrosative and oxidative stress, inflammation and proteolysis in a mouse model of endotoxemia and mechanical ventilation.

Results: Mechanical ventilation and endotoxemia increased expression of inducible nitric oxide synthase (iNOS) mRNA and cytokine levels of interleukin (IL)-1β, IL-6 and keratinocyte-derived chemokine, and decreased IL-10, in the diaphragm; however, they had no effect on protein nitrosylation and 4-hydroxy-2-nonenal protein concentrations. Levosimendan decreased nitrosylated proteins by 10% (P <0.05) and 4-hydroxy-2-nonenal protein concentrations by 13% (P <0.05), but it augmented the rise of iNOS mRNA by 47% (P <0.05). Levosimendan did not affect the inflammatory response in the diaphragm induced by mechanical ventilation and endotoxemia.

Conclusions: Mechanical ventilation in combination with endotoxemia results in systemic and diaphragmatic inflammation. Levosimendan partly decreased markers of nitrosative and oxidative stress, but did not affect the inflammatory response.